Targeted covalent inhibitors and chemical probes have become integral parts of drug
discovery approaches. Given the advantages of fragment-based drug discovery, screening
electrophilic fragments emerged as a promising alternative to discover and validate
novel targets and to generate viable chemical starting points even for targets that
are barely tractable. In this review, we present recent principles and considerations
in the design of electrophilic fragment libraries from the selection of the appropriate
covalent warhead through the design of the covalent fragment to the compilation of
the library. We then summarize recent screening methodologies of covalent fragments
against surrogate models, proteins, and the whole proteome, or living cells. Finally,
we highlight recent drug discovery applications of covalent fragment libraries.
